The long term goal of this project is to characterize some of the presynaptic mechanisms used by the nervous system to adapt to the changing needs of the organism which we assume result from changes in synaptic efficacy--the process by which one neuron signals to another. Of particular interest are changes in synaptic efficacy which have long time courses and which are use-dependent. In the brain these mechanisms may serve higher functions such as learning and memory, but they must also play important adaptive roles in the peripheral, autonomic nervous system. Do they come into play during stress to assist the cardiovascular system make appropriate adjustments? Is it possible that these adjustments may become maladaptive and contribute to a stress syndrome and sudden cardiac death? This application proposes a study of synapses in sympathetic ganglia that regulate cardiovascular function. These synapses exhibit many of the properties of synapses in the brain but can be studied in isolation and under much more rigorous experimental conditions. A brief period of presynaptic tetany results in a long term potentiation of both nicotinic and muscarinic synaptic transmission in the superior cervical ganglion. Specifically, we will study the effects of selected modulators of nervous activity on the release of newly synthesized acetyl choline (ACh). LTP induced by tetanic stimulation produces an increased release of ACh, and we will determine whether other methods of inducing LTP, e.g., high K+ concentration, exposure to forskolin. cAMP and its analogues, as well as the adrenergic agent, isoproterenol, also increase ACh release by a common mechanism. In addition, we will explore the possibility that a synaptosomal preparation derived from this ganglion will provide a simpler model for the study of cholinergic function. Finally, a new investigation into the molecular mechanisms involved in the induction and maintenance of LTP will center around specific phosphorylated proteins and/or peptides in this tissue. The appearance of such compounds has been correlated with LTP in CNS preparations, however it is never been demonstrated in the peripheral nervous system or in sympathetic ganglia.